As indicated by NCMRR, the primary goal of patient-oriented research is to develop the ?scientific knowledge necessary to enhance the health, productivity, independence, and quality- of-life of people with disabilities.? Multiple sclerosis (MS) is a prevalent and chronic neurologic disease that impacts individuals on many levels. Exercise holds a multitude of benefits for persons with MS (PwMS), including improved physical function, reduced fatigue, improved mood, and improved cognition. There is now evidence from pre-clinical models for neural-level benefits of exercise including increased BDNF, and reduced myelin and axonal damage. But exercise only works if people do it, and many PwMS are deterred from exercising by overheating, exhaustion, and symptom worsening: ?Uhthoff?s phenomenon.? Our group extended Uhthoff?s observation by providing the first-ever report of elevated resting body temperature and its link to worse fatigue in persons with MS; that is, even before exercise, PwMS are already ?heated up.? This R21 will support a trial of aspirin as a pretreatment for exercise: our pilot data collected in 12 participants show improved exercise performance and reduced exercise-induced body temperature increase after aspirin. For the proposed study, sixty MS patients will be enrolled in a double-blind RCT with three arms: placebo, aspirin, and acetaminophen (APAP). Design is crossover: each participant will complete three exercise sessions separated by 1-week intervals. At each session, body temperature will be measured before administration of a standard adult dose (two 325-mg capsules) of aspirin, APAP, or placebo. One hour later (time to reach peak serum level) participants will complete a progressive ramped maximal exercise test on a lower body cycle ergometer. Body temperature and biophysical/behavioral variables (VO2max, total watts achieved, blood pressure, anaerobic threshold, ratings of perceived exertion) will be recorded throughout the test at regular intervals. Past research in MS has found cooling treatments (cooling garments, vacuum hand-cooling chambers) effective for improving exercise performance. However, their widespread adoption for research / clinical use is limited by practicality and lack of standardization. Aspirin is a simple, readily available, cost-effective treatment that does not require FDA approval. If successful, this R21 grant may motivate change in clinical care and adoption of ASA therapy for enhancing exercise performance in PwMS. Positive findings from this study will facilitate future research to test whether ASA use improves exercise adherence, increases everyday physical activity levels, and improves overall QOL for persons with MS.